Purpose:
The purpose of this study was to assess the diagnostic power of the novel two-dimensional parameter Bruch's membrane opening minimal rim area (BMO-MRA) in spectral-domain optical coherence tomography (SD-OCT) for detection of glaucoma compared to minimal rim width (BMO-MRW) and retinal nerve fiber layer (RNFL) thickness in large and small optic discs.

Methods:
In this case-control, cross-sectional study, 207 eyes of 207 participants, including 89 controls and 97 patients with glaucoma and 21 with ocular hypertension (OHT), with a disc size <1.63 mm2 or >2.43 mm2 underwent SD-OCT, confocal laser scanning tomography (CSLT), visual field testing, and clinical examination. Bruch's membrane opening-MRA BMO-MRW, RNFL thickness of SD-OCT and disc margin rim area (DM-RA) of CSLT were evaluated and analyzed for diagnostic power to detect glaucoma.

Despite major advantages in glaucoma diagnostics compared to preceding techniques, BMO-based morphometry using one-dimensional parameters (i.e., BMO-MRW) has important limitations. Normative BMO-MRW values depend on disc size, especially in large optic discs BMO-MRW is physiologically thinner. Recently, morphometric data for eyes with nonglaucomatous macrodiscs have been published.19 Other less frequent ONH configurations (e.g., conus, myopic disc) require matching with a specific control group of healthy individuals to achieve high diagnostic power. Malik et al.21 published an analysis of the diagnostic power in myopic discs; Enders et al.22 assessed the diagnostic power of one-dimensional SD-OCT-based morphometric parameters in microdiscs independently of refractive status.

As an advancement of the technique, Gardiner et al.1 introduced the two-dimensional parameter BMO-based minimum rim area (BMO-MRA), analyzing 221 eyes. Those authors concluded that MRA measurements using SD-OCT are significantly better correlated to both RNFL thickness and mean deviation in visual field testing than rim measurements within the BMO plane or based on the clinical disc margin. Additionally, BMO-MRA is supposed to equalize rim width differences between very small ONHs and very large ONHs. In calculating BMO-MRA, disc size serves as an input parameter and should compensate for differences in minimum neuroretinal rim width related to disc size.

The present study's purpose was to assess the diagnostic power of BMO-based MRA measurements in individuals with very small and very large ONHs, referred to as microdiscs (<1.63 mm2 in CSLT) and macrodiscs (> 2.43 mm2 in CSLT), respectively. Bruch's membrane opening-MRA was calculated by a newly developed OCT evaluation software. We aimed to verify the hypothesis that the novel parameter BMO-MRA neutralizes the effect of disc size on one-dimensional morphometric parameters. We also aimed to assess the diagnostic power of BMO-MRA to differentiate healthy small/large ONHs from those with glaucomatous damage compared to BMO-MRW, RNFL thickness (OCT), and rim area (CSLT). The study cohort consisted of nonglaucomatous individuals and glaucomatous patients examined at the center.

Methods

Data for this single-center retrospective analysis were acquired between September 2014 and February 2016 at the Department of Ophthalmology, University Hospital of Cologne, Germany. Patients in whom both CSLT and SD-OCT measurements of the optic nerve head were made on the same day were screened for disc size. Additional parameters were collected from patients' files, including ophthalmologic diagnoses, previous surgery (especially if antiglaucomatous), best-corrected visual acuity, IOP at examination and maximal IOP, topical medication, and medical history of the eyes. Intraocular pressure was assessed by corneal rebound tonometry (TA01i tonometer, Icare Finland Oy, Vantaa, Finland) in adults and children, respectively, and by Goldmann tonometry. All patients included in this study were patients examined at our center. Individuals with no suspicion of glaucoma underwent ONH morphometry and visual field testing as part of a full screening for ocular diseases or for exclusion of glaucoma or ocular hypertension (OHT), mainly on a private medical practice basis.

Inclusion and Exclusion Criteria

Eyes with small optic discs of less than 1.63 mm2 in CSLT, as well as those with a large optic disc of more than 2.43 mm2 in CSLT, were included in this study. This threshold was set by exceeding the lower or upper limit for the normative collective in CSLT according to CSLT software version 3.1.0.2. The exclusion criteria were visual field loss for causes other than glaucoma; unsatisfactory image quality in CSLT, OCT, or in visual field testing; and best-corrected visual acuity >0.4 logMAR (Snellen equivalent: 20/50). The interval of SD-OCT/CSLT assessment and visual field testing should not have exceeded ± 28 days. For nonglaucomatous individuals, a mean deviation of better than −3 dB was required. If multiple data points at different time points were available, the examination with the best imaging quality indicators was used. If both eyes fulfilled all inclusion criteria and no exclusion criteria, the eye with the smaller or respectively larger disc size was selected.

Diagnosis of Glaucoma

Patients were divided into one of three diagnostic groups according to the Guidelines of the European Glaucoma Society (EGS)23: glaucoma patients, patients with OHT, and individuals with no suspicion of glaucoma.

In EGS guidelines, glaucomas are progressive optic neuropathies which have common characteristic morphologic changes at the ONH and RNFL in the absence of other ocular diseases or congenital anomalies. Progressive ganglion cell death and visual field loss are associated with these changes. For glaucoma patients included in the present study, beginning changes in visual field assessment were required. Perimetric data were reviewed manually for glaucomatous changes according to EGS guidelines.23 Perimetric data were reviewed manually for glaucomatous changes according to EGS guidelines. Comprehensive grading and screening for glaucomatous defects in visual field consisted of evaluation of mean deviation, mean pattern standard deviation, grayscale map, Bebié curve, and pattern deviation probability maps.

Morphometric Analyses of the Optic Disc

CSLT and SD-OCT examinations were performed (Heidelberg Engineering Retina Tomograph III and Spectralis-SD-OCT; Heidelberg Engineering) in accordance with standard operating procedures. Two independent evaluators (EP, SF) assessed image quality and, in CSLT, defined the disc margin manually; the threshold for the standard deviation of the CSLT topography was set at <40 μm. Data included in OCT consisted of an image quality index of >15 dB. The neuroretinal rim was calculated automatically by using the CSLT standard reference plane. Spectral-domain OCT imaging was performed with a commercially available OCT device. A light source of 870 nm was used according to standard imaging procedure. The scanning pattern was centered on the BMO with radial equidistance (24-high resolution, 15° radial scans, each averaged from 27 B-scans). The examiners controlled the centration of the scan to the optic disc and corrected errors in detection of ILM and BMO. Optical coherence tomography-based parameters were calculated using the device-operating software tool provided by the manufacturer, including provision of a data export batch.

Bruch's membrane opening-MRA calculation was performed by the manufacturer's software, Spectralis SP-X VWM (Heidelberg Engineering), provided without charge. Gardiner et al.1 proposed the principle of BMO-MRA calculation. Bruch's membrane opening-MRA is described as the minimum surface spanned between BMO and ILM (Fig. 1). The minimum surface tends to be approximately perpendicular to the direction of nerve fibers traversing the ONH. Thus, the minimum surface tends to correlate with the total number of nerve fibers traversing the optic nerve. In BMO-MRA, the analog to procedures in one-dimensional morphometric parameter MRW, the calculation software used localized minimization of every radial scan independently of other sectors.

Principle of standardized BMO-MRA calculation software Spectralis SP-X VWM. Note in the graphical model: between every two B-scans, local BMO-based minimum rim area is calculated as a trapezoid covering the minimum area between the ILM and BMO. Global and sectorial BMO-MRA are determined by addition of respective local minimum rim area results.

Figure 1

Principle of standardized BMO-MRA calculation software Spectralis SP-X VWM. Note in the graphical model: between every two B-scans, local BMO-based minimum rim area is calculated as a trapezoid covering the minimum area between the ILM and BMO. Global and sectorial BMO-MRA are determined by addition of respective local minimum rim area results.

Visual field testing was performed using a visual field analyzer (Octopus 101, Haag-Streit AG, Koeniz, Switzerland) with a 30-2 tendency-oriented perimetry white-on-white standard pattern. Data analysis was performed using Peridata version 3.1 software (PeriData Software GmbH, Huerth, Germany). Visual field testing was performed separately for both eyes; lens correction matching age and refraction were applied. Thresholds for reliability were set at ≤30% for false positive and false negative answers and at ≤20% for fixation losses. Mean deviation (MD) was analyzed for all patients. Visual field results were screened manually as described above for glaucomatous scotoma and were classified using the method reported by Aulhorn.24–26

Sample Size

The sample size required to detect a clinically relevant improvement of 0.2 in an assumed area under curve (AUC) of 0.7 with power 0.8 and type I error alpha set to 0.05 was estimated to be at least 52 patients in each group.27

Ethics and Statistics

According to national medical regulations for retrospective single-center clinical studies, Ethics Committee of the University of Cologne ruled that approval was not required for this study. All tenets of the Declaration of Helsinki were observed. Statistical analyses were performed using SPSS version 22.0 software (SPSS, IBM Corp. Armonk, NY, USA) and the statistical programming language R version 3.2.2 (R Foundation for Statistical Computing, Vienna, Austria). Pearson's correlation coefficient r value and Spearman rank correlation coefficient rho (ρ) were used depending on normal distribution of parameters. Student's t-test or the Kolmogorov-Smirnov Z test was applied for comparing means depending on normal distribution tested by the Shapiro-Wilk test. Diagnostic power was assessed by the receiver operating characteristic (ROC) analysis and tested for statistically significant differences with the DeLong test for areas under curve. P values for partial areas under curve were estimated by bootstrap. The threshold for statistical significance was set to a P value of <0.05.

Results

A total of 207 eyes of 207 patients were included in this study. Glaucoma was diagnosed in 97 patients (46.9%); OHT was present in 21 patients (10.1%), and 89 individuals (43.0%) showed no clinical suspicion of glaucoma. Epidemiology and baseline data are summarized in Table 1.

(a) Scatter plot of BMO-MRA and mean deviation of visual field function in macro- and microdiscs Note, fitted curves are based on a cubic curve estimation regression model. (b) Scatter plot of BMO-MRW and mean deviation of visual field function in macro- and microdiscs. Note, fitted curves are based on a cubic curve estimation regression model. (c) Scatter plot of RNFL thickness and mean deviation of visual field function in macro- and microdiscs. Note, fitted curves are based on cubic curve estimation regression model.

Figure 2

(a) Scatter plot of BMO-MRA and mean deviation of visual field function in macro- and microdiscs Note, fitted curves are based on a cubic curve estimation regression model. (b) Scatter plot of BMO-MRW and mean deviation of visual field function in macro- and microdiscs. Note, fitted curves are based on a cubic curve estimation regression model. (c) Scatter plot of RNFL thickness and mean deviation of visual field function in macro- and microdiscs. Note, fitted curves are based on cubic curve estimation regression model.

Receiver operating characteristic analyses were performed to assess and compare the diagnostic power of the morphometric parameters in this study. Because of the statistically confirmed congruence of baseline ONH parameters, OHT patients were added to the control group. For the entire group of 207 eyes, the calculated AUC results and sensitivity at 95% specificity to differentiate glaucoma patients from controls were 0.89 and 62% for BMO-MRA, 0.86 and 47% for DM-RA, 0.84 and 52% for RNFL thickness, and 0.80 and 54% for BMO-MRW (Table 4). AUC for BMO-MRA was significantly larger compared with BMO-MRW (P < 0.001) and with RNFL thickness (P = 0.02, Table 5). Regarding partial AUC (pAUC) for specificities between 0.8 and 1, pAUC of BMO-MRA was significantly larger than all three other morphometric parameters with P < 0.001 in comparison BMO-MRW, P = 0.03 compared to RNFL thickness, and P = 0.01 compared to DM-RA (Table 6). Cutoff points at 95% specificity were 0.78 mm2 for BMO-MRA, 166.09 μm for BMO-MRW, 54.00 μm for RNFL, and 0.83 mm2 for DM-RA in CSLT.

In macrodiscs, matching disc sizes in the control group showed a further increase in AUC to 0.96 for BMO-based minimum rim area measurement. In microdiscs, compared to other morphometric parameters, the BMO-MRA AUC was highest at 0.83. Separate analysis of participants with macrodiscs or with microdiscs shows a major decrease of the difference in AUC and pAUC between BMO-MRA and BMO-MRW (Table 4). Figure 3 illustrates ROC analysis for all morphometric parameters analyzed in this study.

With increasing use of BMO-based SD-OCT in glaucoma diagnostics, the ability of different morphometric parameters to differentiate glaucomatous damage is analyzed and challenged for different ONH characteristics.8–10 These are small or large discs, myopic discs, tilted disc, and other papillary anomalies. While Malik et al.21 tested 130 individuals with myopic discs, we recently published reference data for 102 controls in SD-OCT analysis in nonglaucomatous large optic discs.19,21

Bruch's membrane opening-MRW of all the commercially available parameters, has been shown to have the highest sensitivity in discrimination of glaucoma patients from normal controls.9 Bruch's membrane opening-based minimum rim area (BMO-MRA) analysis has been proposed as the next step in advancement of the technique.1,12 The findings of the present study of BMO-MRA assessment in macro- and microdiscs allow the following conclusions. For a study group consisting of the full range of very large and small disc sizes, BMO-MRA offers superior diagnostic power to detect glaucoma compared to other currently used morphometric parameters. For a mixed group of micro- and macrodiscs, the SD-OCT parameters BMO-MRW and RNFL thickness do not significantly exceed the CSLT parameter DM-RA in diagnostic power. For microdiscs only, superiority of SD-OCT-based BMO-MRW and RNFL thickness measurements compared with CSLT evaluation could already be shown.22 Therefore, for one-dimensional morphometric parameters, adapting the control group regarding disc size seems crucial to improve diagnostic power. The reasoning behind this is that normative values vary significantly with disc size.

The parameter BMO-MRA offers comparability in assessment of neuroretinal rim tissue between large differences in discs sizes. Overall sensitivities at 95% specificity and AUC results are in line with the published data of Chauhan et al.,10 Malik et al.,21 and the best correlation of BMO-MRA and mean deviation in visual field testing are similar to the results published by Gardiner et al.1

The structure-function relationship correlated at high significance levels, implying the superiority of BMO-based parameters in correlation to mean deviation in visual field testing. In other studies, the structure-function relationship varied for different examination techniques, diagnoses, and patients' characteristics.11,28–30 Gardiner et al.31 recently showed that peripapillary RNFL thickness may be superior compared with BMO-MRW and BMO-MRA in follow-up assessment of glaucoma patients by higher correlation to progression of visual field defects. For macro- and microdiscs, that hypothesis needs to be tested in a follow-up study.

Limitations of our study include the retrospective study set up and potential selection bias as a result of patient exclusion because of data inconsistencies or lacking image quality. The relatively large sample size in the present study reduces this possible bias. Controls were recruited from nonglaucomatous patients examined at our center, fulfilling all inclusion and no exclusion criteria of this study. In consequence, data for our patients may not be fully representative in an epidemiologic context. Availability of prospective data on normal micro- and macrodiscs is limited. Further prospective studies in normal controls also analyzing individuals with macro- and microdiscs would be helpful. Bruch's membrane opening-based minimum rim area was calculated using localized minimization of the minimum surface spanned between BMO and ILM. Hence, this approach may not accurately reflect the true total minimum area through which the nerve fibers pass. Modifications of BMO-MRA calculation using globalized optimization where one optimization is performed in all (typically 48) degrees of freedom simultaneously, need to be evaluated in future studies.

To summarize the main conclusions of the present study, BMO-MRW is significantly different between small and large discs in nonglaucomatous normal controls. Novel two-dimensional BMO-MRA equalizes disc size dependency, as it serves as an input factor to calculate the rim area. Furthermore, BMO-MRA surpasses other parameters in diagnostic power to detect glaucoma in a mixed group of small and large optic discs. Integration in the routine evaluation software could improve diagnostic performance of the technique and should be considered by the manufacturer.

Acknowledgments

The authors thank the technical experts in our imaging laboratory and those for 2240 “(Lymph-) Angiogenesis And Cellular Immunity In Inflammatory Diseases Of The Eye” for their support.

Principle of standardized BMO-MRA calculation software Spectralis SP-X VWM. Note in the graphical model: between every two B-scans, local BMO-based minimum rim area is calculated as a trapezoid covering the minimum area between the ILM and BMO. Global and sectorial BMO-MRA are determined by addition of respective local minimum rim area results.

Figure 1

Principle of standardized BMO-MRA calculation software Spectralis SP-X VWM. Note in the graphical model: between every two B-scans, local BMO-based minimum rim area is calculated as a trapezoid covering the minimum area between the ILM and BMO. Global and sectorial BMO-MRA are determined by addition of respective local minimum rim area results.

(a) Scatter plot of BMO-MRA and mean deviation of visual field function in macro- and microdiscs Note, fitted curves are based on a cubic curve estimation regression model. (b) Scatter plot of BMO-MRW and mean deviation of visual field function in macro- and microdiscs. Note, fitted curves are based on a cubic curve estimation regression model. (c) Scatter plot of RNFL thickness and mean deviation of visual field function in macro- and microdiscs. Note, fitted curves are based on cubic curve estimation regression model.

Figure 2

(a) Scatter plot of BMO-MRA and mean deviation of visual field function in macro- and microdiscs Note, fitted curves are based on a cubic curve estimation regression model. (b) Scatter plot of BMO-MRW and mean deviation of visual field function in macro- and microdiscs. Note, fitted curves are based on a cubic curve estimation regression model. (c) Scatter plot of RNFL thickness and mean deviation of visual field function in macro- and microdiscs. Note, fitted curves are based on cubic curve estimation regression model.